期刊
MUCOSAL IMMUNOLOGY
卷 13, 期 4, 页码 665-678出版社
ELSEVIER SCIENCE INC
DOI: 10.1038/s41385-020-0259-9
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资金
- National Institutes of Health [DK50984, DK069854, T32DK083251, P30DK097948 Pilot, K08DK110415]
- Digest Science
- Deutsche Forschungsgemeinschaft [RI1735/2-1]
- Crohn's and Colitis Foundation of America [2308]
- National Center for Advancing Translational Sciences of the National Institutes of Health [UL1TR000439]
- European Crohn's and Colitis Organization
- Departments of Colorectal Surgery and Pathology of the Cleveland Clinic
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [K08DK110415] Funding Source: NIH RePORTER
Intestinal fibrosis leading to strictures remains a significant clinical problem in inflammatory bowel diseases (IBD). The role of bacterial components in activating intestinal mesenchymal cells and driving fibrogenesis is largely unexplored. Tamoxifen-inducible alpha-SMA promoter Cre mice crossed with floxed MyD88 mice were subjected to chronic dextran sodium sulfate colitis. MyD88 was deleted prior to or after induction of colitis. Human intestinal myofibroblasts (HIMF) were exposed to various bacterial components and assessed for fibronectin (FN) and collagen I (Col1) production. RNA sequencing was performed. Post-transcriptional regulation was assessed by polysome profiling assay. Selective deletion of MyD88 in alpha-SMA-positive cells prior to, but not after induction of, experimental colitis decreased the degree of intestinal fibrosis. HIMF selectively responded to flagellin with enhanced FN or Col1 protein production in a MyD88-dependent manner. RNA sequencing suggested minimal transcriptional changes induced by flagellin in HIMF. Polysome profiling revealed higher proportions of FN and Col1 mRNA in the actively translated fractions of flagellin exposed HIMF, which was mediated by eIF2 alpha and 4EBP1. In conclusion, selectivity of flagellin-induced ECM secretion in HIMF is post-transcriptionally regulated. The results may represent a novel and targetable link between the gut microbiota and intestinal fibrogenesis.
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